. عبد. أحمد د . أ عبد. أحمد د أالسالمالسالم

Once a specific cause of infection is identified based upon specific microbial tests, the following questions should be considered:1. If a specific microbial pathogen is identified, can a narrower spectrum agent be substituted for the initial empirical therapy?2. Is one agent or a combination of agents necessary?3. What is the optimal dose, route of administration, and duration of therapy?4. What adjunctive measures can be undertaken to eradicate the infection? For example is surgery feasible for removal of devitalized tissue or foreign body or drainage of an abscess- into which antimicrobial agents may be unable to penetrate?

Choice of antimicrobial agent depends uponI. Host factors: History of allergy- renal and hepatic function-

resistance to infection (ie whether immuno-compromised)- ability to tolerate drugs by mouth- severity of illness- age- and if female whether pregnant, breast-feeding or taking oral contraceptive.Patients with AIDS have an unacceptably high risk of allergic and toxic reactions to many antimicrobial agents.Patients with severe liver disease have an unacceptably high risk of developing non-oliguric renal failure with aminoglycosides.Prior adverse effects and impaired elimination or detoxification of the drug- this may be genetically pre-determined or due to underlying renal or hepatic disease.

The age of the patient at times may provide important additional clues to the likely organism or may affect the choice of the antimicrobial:In meningitis, neonates are usually infected with group B streptococcus or enteric organisms.In children younger than 2 years, H.influenza is common but S. pneumoniae and Neisseria meningitidis also occur. The last two organisms are the most common pathogens in adults.The duration of therapy, dosage and route of administration depend on site, type and severity of infection and response.The dose varies according to a number of factors including age, weight, renal function and severity of infection.

II. Pharmacologic factors:. The kinetics of absorption, distribution and elimination.. The ability of the drug to be delivered to the site of infection.. The potential toxicity of an agent.. The pharmacokinetic or pharmcodynamic interaction with other drug.Pharmacokinetic differences among agents with similar antimicrobial spectrum may be exploited to decrease the frequency of dosing (e.g. ceftriaxone may be conveniently given every 24 hours).

III. Lastly, increasing consideration is being given to cost of antimicrobial therapy especially when multiple agents with comparable efficacy are available for a specific infection.

Interpretation of culture results Properly obtained and processed specimens for culture

frequently yield reliable information. The lack of a confirmatory microbial diagnosis may be due to:

1. Sample error,e.g. obtaining culture after antimicrobial agents have been administered.

2. Non-cultivable or slowly growing organisms, where cultures are discarded before sufficient growth.

3. Requesting bacterial cultures when the infection is due to other organisms.

4. Not recognizing the need for special media or isolation techniques.

Susceptibility testingTesting bacterial pathogens in vitro for their susceptibility, ideally to a narrow-spectrum, non-toxic antimicrobial drug.Tests measure the concentration of drug required to inhibit growth of thr organism (MIC) or kill the organism (MBC). The results can be correlated to known drug concentration in various body compartments.Only MICs are routinely measured in most infections, where in infections in which bactericidal therapy is required for irradication (e.g. meningitis, endocarditis, sepsis in the granulocytopenic patient), MBC measurements may be useful.

Clinical failure of antimicrobial therapy. Errors in susceptibility testing are rare, but the original results should be confirmed by repeated testing.. Drug dosing and absorption should be scrutinized and tested directly using serum measurements. Pill counting or directly observed therapy.. The clinical data should be reviewed to determine whether the patient’s immune system is adequate, and if not, what can be done to maximize it. For example, are adequate number of granulocytes present and are HIV infection, malnutrition, or underlying malignancy present?. The presence of abscesses or foreign bodies should also be considered.. Culture and susceptibility testing should be repeated to determine if superinfection has occurred with another organism- or if the original organism becomes resistant.

Antimicrobial Pharmacodynamics

Pharmacodynamic factors include1. pathogen susceptibility testing2. Drug bactericidal versus bacteriostatic activiy3. Drug synergism or antagonism4. Post-antibiotic effectTogether with pharmacokinetics, pharmaco-dynamic information permits the selection of antimicrobial dosage regimens.

Bacterioststic versus bactericidal activity. This classification has limitations: Some agents that are considered bacteriostatic may be bactericidal against selected microorganisms. For example chloramphenicol is often bactericidal against pneumococci, meningococci, and H.influenza. On the other hand, enterococci are inhibited, but not killed, by vancomycin, penicillin or ampicillin, used as single drugs.

. Static and cidal agents are equivalent for treatment of most infections in immunocompetent host. Cidal agents should be selected over static ones when local or systemic host defenses are impaired. Cidal agents are required for treatmnt of meningitis, endocarditis and other endovascular infections and infections in neutropenic cancer patients.

Bactericidal agents can be divided into two groups:

1. Agents that exhibit concentration-dependent killing (e.g. aminoglycosides, quinolones) with which the rate and extent of killing increase with increasing drug concentration, i.e. increasing concentrations kill an increasing proportion of bacteria and at a more rapid rate.Maximizing peak serum concentration of such drugs results in increased efficacy and decreased selection of resistant bacteria.Concentration dependent killing is one of the pharmacodynamic factors responsible for the efficacy of once-daily dosing of aminoglycosides.

2. Agents that exhibit time-dependent killing (e.g. Beta lactams and vancomycin) do not exhibit increasing killing with increasing concentraion above MBC. Antibacterial activity is directly related to time above MBC and becomes independent of concentration once the MBC has been exceeded. Bactericidal activity continues so long as serum concentrations are greater than MBC.

Drug concentration of time-dependent killing agents that lack a post-antibiotic effect should be maintained above the MBC for the entire dosage interval.

Postantibiotic effect “PAE”It is the persistent suppression of bacterial growth after limited exposure to an antimicrobial agent, ie. Antimicrobial activity persists beyond the time that measurable drug is present. It is expressed mathematically as follows: PAE = T – CT= time required for the viable count in the test (in vitro) culture to increase tenfold above the count observed immediately before drug removal.C= time required for the count in untreated culture to increase tenfold above the count observed immediately after completion of the same procedure used in the test culture.The PAE reflects the time required for bacteria to return to logarithmic growth. It may represent an extension of the lag phase of bacterial growth.

Proposed mechanisms of PAE:1. Recovery after reversible non-lethal damage to cell

structures.2. Persistence of drug at a binding site or within periplasmic

space.3. The need to synthesize new enzymes before growth.4. In-vivo PAE is thought to be due to postantibiotic

leukocyte enhancement (PALE).

Most antimicrobials possess in vitro PAE (> 1.5 h) against susceptible gram positive cocci. Antimicrobials with significant PAE against susceptible gram negative bacilli are limited to carbapenems, and agents that inhibit protein or DNA synthesis.

Antimicrobials with in vitro PAE > 1.5 h

Against gram positive cocci: Aminoglycosides, carbapenems, cephalosporins, chloramphenicol, clindamycin, macrolides, oxazolidinones, penicillins, quinolones, rifampicin, sulphonamides, tetracyclines, trimethoprim, vancomycin.

Against gram negative bacilli: Aminoglycosides, carbapenems, chloramphenicol, qinolones, rifampicin, tetracyclines

In-vivo PAEs are usually much longer than in vitro PAEs. This may be due to postantibiotic leucocyte enhancement (PALE) and exposure of bacteria to subinhibitory antibiotic concentrations.PALE reflects the increased susceptibility of bacteria to the phagocytic and bactericidal action of neutrophils.Subinhibitory drug concentrations result in altered bacterial morphology and decreased rate of growth.

The lowest drug concentration required to induce morphologic changes is known as the minimal antibacterial concentration.

Clinical relevance of PAE:Aminoglycosides have significant PAE that can reach several hours.Aminoglycosides and quinolones possess concentration dependent PAEs; thus high doses of aminoglycosides given once daily result in enhanced bactericidal activity and extended PAEs. These pharmacodynamic effects allow amioglycoside serum concentrations that are below the MICs of target organisms to remain effective for extended periods of time.Aminoglycoside toxicity is both time- and concentration-dependent. Toxicity is unlikely to occur until a certain threshold concentration is achieved, but once it is achieved the time above this threshold becomes critical.At clinically relevant doses the time above the threshold is greater with multiple smaller doses than with a single large dose.

Advantages of once-daily dosing:1. A single daily dose of aminoglycosides is just as

effective and no more (often less) toxic than multiple smaller doses.

2. Avoidance of adaptive resistance, a phenomenon in which reduced bactericidal activity occurs following a second antibiotic exposure. It is probably caused by a reduction in energy-dependent aminoglycoside uptake into bacteria.

3. Lower monitoring cost than conventional dosing. No need to obtain serum concentrations unless the intention is to administer aminoglycosides for more than 4-5 days.

N.B. The use of once-daily dosing does not eliminate careful monitoring and dose adjustment to minimize toxicity (accoding to creatinine clearance).

Pharmacokinetic considerationsRoute of administrationIn critically ill patients oral or IM absorption is unreliable. The IV route is preferred in such patients. IV therapy is also preferred in bacterial meningitis or endocarditis.Parenteral therapy should be selected in patients with nausea, vomiting, gastrectomy or diseases that affect GI absorption. This route is also preferred for drugs such as vancomycin and antipsudomonas penicillin which are poorly absorbed from GIT.However, many antimicrobials have similar pharmacokinetic properties when given orally or parenterally (tetracycline, cotrimoxazole, quinolones, chloramphenicol, metronidazole, clindamycin, rifampin, fluconazole). In most cases, oral therapy with these drugs is equally effective, less costly and with fewer complications.

Conditions that alter antimicrobial pharmacokineticsVarious diseases and physiologic states alter the pharmacokinetics of antimicrobial drugs.Impairment of renal or hepatic function may result in decreased elimination. Dosage adjustment is necessary in these situations to avoid toxicity.Conversely patients with burns, cystic fibrosis, or trauma may have increased dosage requirements for selected agents.The pharmacokinetics of antimicrobialsare also altered in the eldely, in neonates and in pregnancy.

Dosage adjustment needed in hepatic impairment: Chloramphenicol, clindamycin, erythromycin, amprenavir, indinavir, rimantadine, metronidazole.

Dosage adjustment needed in renal impairmentAcyclovir, amantadine, aminoglycosides, aztreonam, cephalosporins (except cefoperazone and ceftriaxone), clathromycin, cycloserine, didanosine, ethambutol, famciclovir, fluconazole, flucytosine, foscarnet, ganciclovir, imipenem, lamivudine, meropenem, penicillins (except antistaph, e.g. nafcillin and dicloxacillin), quinolones, rimantadine, atavudine, terbenafine, cotrimoxazole, valacyclovir, vancomycin, zalcitabine, zidovudine.

Antimicrobials contraindicated in renal impairment:Cidovovir, methenamine, nalidixic acid, nitrofurantoin, sulfonamides (long acting), tetracyclines (except doxycycline and possibly minocycline).

Drug concentrations in body fluids:Most antimicrobial agents are well distributed to most body tissues and fluids. Penetration into the CSF is one important exception; clindamycin, aminoglycosides and first and some second generation cephalosporins penetrate poorly.Many antibiotics do not penetrate uninflamed meninges to an appreciable extent. In the presence of meningitis, however the CSF concentration of many antibiotics increase.Two other sites of poor penetration are the prostate and the obstructed biliary tree.The pH of the site of infection may affect antibiotic activity: Aminoglycosides are much more effective at physiologic pH (7.4) than in acid environment (e.g abscess). In pus or sputum, an acid pH may alter the activity of these antibiotics.

CSF penetration of selected antimicrobials (percent of serm concentration):Antimicrobial uninflamed inflamed meningesAmpicillin 2-3 2-100Aztreonam 2 5Cefotaxime 22.5 27-36Ceftazidime 0.7 20-40Ceftriaxone 0.8-1.6 16Cefuroxime 20 17-88Ciprofloxacin 6-27 26-37Imipenem 3.1 11-41Meropenem 0-7 1-52Nafcillin 2-15 5-27Penicillin-G 1-2 8-18Sulphamethoxazole 40 12-47Trimethoprim <41 12-69Vancomycin 0 1-53

Pregnancy and Lactation:Certain drugs may pose special problems (e.g. the tetracycline which may cause hepatotoxicity to the mother and dentition problems in the infant).Placental transfer of antibiotics:Whenever possible, pregnant women should avoid all drugs because of the risk of fetal toxicity:. Antibiotics considered safe in pregnancy include the penicillins, cephalosporins, erythromycin base and probably aztreonam. Antibiotics to be used with caution include the aminoglycosides, vancomycin, clindamycin, imipenem-cilastatin, trimethoprim and nitrofurantoin.. Antibiotics contraindicated in pregnancy include chloramphenicol, erythromycin estolate, tetracycline, fluoroquinolnes, cotrimozazole, metronidazole and sulfonamides.

Placental transfer of antibiotics (infant-maternal serum concentration):

50-100% :Ampicillin, carbenicillin, chloramphenicol, methicillin, nitrofurantoin, penicillin-G, sulphonamides, tetracyclines, trimethoprim.

30-50% :Amphotericin-B, cefamandole, cephalothin, clindamycin, gentamycin, kanamycin, streptomycin.

0-30% :Amikacin, cefazolin, ceftriaxone, dicloxacillin, erythromycin, nafcillin, oxacillin, tobramycin

Antibiotics in breast milk:Minimal data are available regarding adverse effects in nursing neonates.

If possible nursing mothers should avoid all drugs.

The total daily dose a nursing baby receives is often probably not toxicologically significant.

As in pregnancy, chloramphenicol, tetracycline, sulphonamides and metronidazole should be avoided.Until further data are available, it is suggested to avoid the use of fluoroquinolones.

Maternal milk Antibiotic milk concPlasma conc (ug/ml)50-100% Ampicillin NA

Chloramphenicol* 16-25Clindamycin NAErythromycin 0.4-1.6Isoniazid 6-12Metronidazole* NASulfapyridne* 30-130Tetracycline* 0.5-2.6Cotrimoxazole NA

<30% Cefotaxime NACefazolin 1.5Kanamycin* 18.4Nalidixic scid* 4Oxacillin 0.2Penicillin-G 0.01-0.04Streptomycin* 0.3-1.3

--------------------------------------------------------------------------------*Potential toxicity to the mother NA= not available

Monitoring serum concentration of antimicrobial agent

For most antimicrobial agents, the relationship between dose and therapeutic outcome is well established and serum concentration monitoring is unnecessary for these drugs.

In clinical practice, serum concentration monitoring is routinely performed on patients receiving aminoglycosides.

Despite the lack of supporting evidence for its utility or need, serum vancomycin concentration monitoring is also performed.

Flucytosine serum concentration monitoring has been shown to reduce toxicity when doses are adjusted to maintain peak concentration below 100ug/ml.

Antimicrobial combinationAlthough indications for combination therapy exists,

antimicrobial combinations are often overused in clinical practice.

Current indications:1. To provide broad spectrum empirical therapy in

seriously ill patients.2. To treat polymicrobial infections such as

intrabdominal sepsis or pelvic abscess.3. Limiting or preventing the emergence of resistant

strains as in tuberculosis.4. Synergism: Mechanisms:

a) Blockade of sequential steps in a metabolic sequence, eg. Cotrimoxazole.b) Inhibition of enzymatic activation.c) Enhancement of antimicrobial uptake, e.g. cell wall active agents increase the uptake of aminoglycosides.

Commonly used antimicrobial combinations:1. Penicillin and gentamycin are synergistic against S.

especially S.viridans and enterococci.2. Antipseudomonas penicillins and aminoglycosides are

synergistic.3. Cephalosporins and aminoglycosides are synergistic

against K. pneumoniae.4. Sulfamethoxazole and trimethoprim are synergistic

against some gram positive and negative organisms.5. Penicillins and cephalosporins are synergistic with beta-

lactamase inhibitorsas clavulanic acid and sulbactam.6. Flucytosine and Amphotericin-B in cryptococcal

meningitis to reduce the dose of amphotericin-B.7. Unique dug combination; imipenem-cilastatin. The

enzyme inhibitor cilastatin prevents metabolic breakdown of imipenem by the kidney.

Disadvantages of multiple antibiotics:1. An increased risk of drug sensitivities or toxicity.2. Increased cost.3. False sense of security: The use of multiple agents to

cover all possible organisms is often not possible, practical or necessary and may be associated with significant complications.

4. An increased risk of colonization with a resistant organism may occur. If superinfection develops, this organism is difficult to treat.

5. Possibility of antagonism:The most striking example was reported in a study of patients with pneumococcal meningitis who were treated with a combination of penicillin and chlortetracycline. The mortality rate was 79% versus 21% in patients who received penicillin monotherapy.

Mechanisms of antagonistic action:1. Inhibition of cidal activity by static action:

a) Tetracycline and chloramphenicol can antagonize the action of bactericidal of cell wall active agents (beta-lactam antibiotics) whose action requires that the bacteria be actively growing and dividing.b) Tetracycline and chloramphenicaol can also antagonize the bactericidal action of aminoglycosides by inhibition of active aminoglycoside uptake by susceptible organisms.

2. Induction of enzymatic activation:Some gram negative bacilli possess inducible beta-lactamases. Beta-lactam antibiotics as imipenem, cefoxitin and ampicillin are potent inducers of beta-lactamase production. If an inducing agent is combined with hydrolyzable beta-lactam, such as piperacillin, antagonism may occur.